Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
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- 作者：Essa Hu ; Roxanne K. Kunz ; Ning Chen ; Shannon Rumfelt ; Aaron Siegmund ; Kristin Andrews ; Samer Chmait ; Sharon Zhao ; Carl Davis ; Hang Chen ; Dianna Lester-Zeiner ; Ji Ma ; Christopher Biorn ; Jianxia Shi ; Amy Porter ; James Treanor ; Jennifer R. Allen
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：November 14, 2013
- 年：2013
- 卷：56
- 期：21
- 页码：8781-8792
- 全文大小：504K
- 年卷期：v.56,no.21(November 14, 2013)
- ISSN：1520-4804
文摘
Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.